Ethyl glutaconate, methylation

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

A soln. of 2-methylimidazole, ethyl 2-cyano-3-ethoxyacrylate, and ethyl cyano-acetate in ethanol refluxed 4 days diethyl 3 amino-2-cyano-4-[(2-methyl-l-imidazolyl)methylene]glutaconate. Y 91%. F. e., mostly with benzimidazole derivatives, s. R. K. Howe, J. Org. Chem. 34, 2983 (1969). 

K added to anhydrous ferf-butanol, followed by abs. ethanol to obtain a clear soln., then by ethyl cyanoacetate, finally by ethyl acetoacetate, and stirred intermittently at room temp, for 1 week diethyl potassio-a-cyano-j -methyl-glutaconate (Y 97%) refluxed 12 hrs. with ethyl iodide and abs. ethanol diethyl y-cyano- -ethyl- -methylglutaconate (Y 74%). F. e. and limitations s. A. S. Bailey and J. S. Brunskill, Soc. 1959, 2554. 

Fig. 10.19 Chromatogram of organic acids extracted using ethyl acetate from the urine of a patient with 3-hydroxy-3-methylglutaric aciduria and separated as their trimethylsilyl derivatives on 5 per cent SE 52 on Chromosorb W (AW-DMCS, 100-120 mesh) using temperature programming from 75°C to 220°C at 2°C min with initial and final isothermal delays of 10 min. Peak identifications are 1, 3-hydroxyisovalerate 2, hydroxycaproate isomer 3, glutarate 4, 3-methylglutarate 5 and 6, 3-methyl-glutaconate peaks 7, adipate 8, 4-phenylbutyrate (internal standard) 9, 3-hydroxy-3-methylglutarate 10, ascorbate. (Redrawn with modifications from Duran ct. a/., 1978)...

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